COVID-19 and the liver: overview.

On 12 March 2020, the WHO declared that the coronavirus disease 2019 (COVID-19) constitutes a pandemic. Cases of liver damage or dysfunction (mainly characterized by moderately elevated serum aspartate aminotransferase levels) have been reported among patients with COVID-19. However, it is currently uncertain whether the COVID-19 related liver damage/dysfunction is due mainly to the viral infection by itself or other coexisting conditions, such as the use of potentially hepatotoxic medications and the coexistence of systemic inflammatory response, respiratory distress syndrome-induced hypoxia, and multiple organ dysfunction. Individuals at high risk for severe COVID-19 are typical of older age and/or present with comorbid conditions such as diabetes, cardiovascular disease, and hypertension. This is also the same profile for those at increased risk for unrecognized underlying liver disease, especially nonalcoholic fatty liver disease. This could make them more susceptible to liver injury from the virus, medications used in supportive management, or hypoxia. So the aim of this review was to illustrate the clinical implications of COVID-19 on the liver in healthy and diseased states as well as the implications of common liver disorders on the outcome of COVID-19.

Liver transplantation recovers hepatic N-glycosylation with persistent IgG glycosylation abnormalities: Three-year follow-up in a patient with phosphomannomutase-2-congenital disorder of glycosylation.

Phosphomannomutase-2-congenital disorder of glycosylation (PMM2-CDG) is the most common CDG and presents with highly variable features ranging from isolated neurologic involvement to severe multi-organ dysfunction. Liver abnormalities occur in in almost all patients and frequently include hepatomegaly and elevated aminotransferases, although only a minority of patients develop progressive hepatic fibrosis and liver failure. No curative therapies are currently available for PMM2-CDG, although investigation into several novel therapies is ongoing. We report the first successful liver transplantation in a 4-year-old patient with PMM2-CDG. Over a 3-year follow-up period, she demonstrated improved growth and neurocognitive development and complete normalization of liver enzymes, coagulation parameters, and carbohydrate-deficient transferrin profile, but persistently abnormal IgG glycosylation and recurrent upper airway infections that did not require hospitalization. Liver transplant should be considered as a treatment option for PMM2-CDG patients with end-stage liver disease, however these patients may be at increased risk for recurrent bacterial infections post-transplant.

Nutritional Approaches in Children with Overweight or Obesity and Hepatic Steatosis.

Childhood obesity is a global public health problem. Worldwide, 41 million children under 5 years and 340 million children and adolescents between 5 and 19 years are overweight. In addition, the recent COVID-19 epidemic has further amplified this social phenomenon. Obesity is a condition associated with various comorbidities, such as nonalcoholic fatty liver disease (NAFLD). The pathophysiology of NAFLD in obesity is intricate and involves the interaction and dysregulation of several mechanisms, such as insulin resistance, cytokine signaling, and alteration of the gut microbiota. NAFLD is defined as the presence of hepatic steatosis in more than 5% of hepatocytes, evaluated by histological analysis. It can evolve from hepatic steatosis to steatohepatitis, fibrosis, cirrhosis, hepatocellular carcinoma, and end-stage liver failure. Body weight reduction through lifestyle modification remains the first-line intervention for the management of pediatric NAFLD. Indeed, studies suggest that diets low in fat and sugar and conversely rich in dietary fibers promote the improvement of metabolic parameters. This review aims to evaluate the existing relationship between obesity and NAFLD in the pediatric population and to assess the dietary patterns and nutritional supplementations that can be recommended to prevent and manage obesity and its comorbidities.

Ivermectin drug induced liver injury.

Ivermectin remains a popular, albeit unproven, therapy used in both the prevention and treatment of COVID-19. We discuss a patient who developed jaundice and a liver injury 3 weeks after initiating ivermectin for COVID prevention.  Liver histology demonstrated a pattern of injury that was both portal and lobular, with a bile ductulitis as well with marked cholesasis. She was managed with low dose corticosteroids, later tapered and withdrawn. She remains well a year after presenting.

Post-COVID-19 Complications and their Laboratory Findings: A Cohort Study.

Type 2 severe acute respiratory syndrome caused by coronavirus infection has become the most well-known pandemic infectious viral disease in the present century. This study aims to find out the post-COVID-19 infection complications via a well-designed observational study. A total of 986 recovered cases (only the period ranged between 2 to 3 months after recovery) were obtained from public and private hospitals in Kirkuk and Erbil governorates\Iraq. The admitted patients were asked to answer a questionnaire through interviews; the laboratory findings were obtained from the patients. The results suggested that approximately half of post-COVID-19 patients (%45.606) were suffering from chest pain, while (%32.357) of the cases suffered headache and chest pain. Liver enzymes (ALT, AST, and ALP) showed abnormal percent values of 38.6,24.07, and 26.09, respectively. Renal function enzymes, mainly urea, were found to be abnormal in 45.37% of recovered individuals. Furthermore, abnormal LDH levels were found in (77.9%) of post-COVID-19 patients. This finding revealed that chest pain was an inflammatory condition and liver and renal enzyme disturbances, while elevation in LDH was the predominant long-term complication in post-COVID-19 patients.

The Prophylactic Effect of Vitamin C and Vitamin B12 against Ultraviolet-C-Induced Hepatotoxicity in Male Rats.

Ultraviolet C (UVC) devices are an effective means of disinfecting surfaces and protecting medical tools against various microbes, including coronavirus. Overexposure to UVC can induce oxidative stress, damage the genetic material, and harm biological systems. This study investigated the prophylactic efficacy of vitamin C and B12 against hepatotoxicity in UVC-intoxicated rats. Rats were irradiated with UVC (725.76, 967.68, and 1048.36 J/cm2) for 2 weeks. The rats were pretreated with the aforementioned antioxidants for two months before UVC irradiation. The prophylactic effect of vitamins against UVC hepatotoxicity was evaluated by monitoring the alteration of liver enzyme activities, antioxidant status, apoptotic and inflammatory markers, DNA fragmentation, and histological and ultrastructural alterations. Rats exposed to UVC showed a significant increase in liver enzymes, oxidant-antioxidant balance disruption, and increased hepatic inflammatory markers (TNF-α, IL-1ß, iNOS, and IDO-1). Additionally, obvious over-expression of activated caspase-3 protein and DNA fragmentation were detected. Histological and ultrastructural examinations verified the biochemical findings. Co-treatment with vitamins ameliorated the deviated parameters to variable degrees. In conclusion, vitamin C could alleviate UVC-induced hepatotoxicity more than vitamin B12 by diminishing oxidative stress, inflammation, and DNA damage. This study could provide a reference for the clinical practice of vitamin C and B12 as radioprotective for workers in UVC disinfectant areas.

Adeno-associated virus 2 infection in children with non-A-E hepatitis.

An outbreak of acute hepatitis of unknown aetiology in children was reported in Scotland1 in April 2022 and has now been identified in 35 countries2. Several recent studies have suggested an association with human adenovirus with this outbreak, a virus not commonly associated with hepatitis. Here we report a detailed case-control investigation and find an association between adeno-associated virus 2 (AAV2) infection and host genetics in disease susceptibility. Using next-generation sequencing, PCR with reverse transcription, serology and in situ hybridization, we detected recent infection with AAV2 in plasma and liver samples in 26 out of 32 (81%) cases of hepatitis compared with 5 out of 74 (7%) of samples from unaffected individuals. Furthermore, AAV2 was detected within ballooned hepatocytes alongside a prominent T cell infiltrate in liver biopsy samples. In keeping with a CD4+ T-cell-mediated immune pathology, the human leukocyte antigen (HLA) class II HLA-DRB1*04:01 allele was identified in 25 out of 27 cases (93%) compared with a background frequency of 10 out of 64 (16%; P = 5.49 × 10-12). In summary, we report an outbreak of acute paediatric hepatitis associated with AAV2 infection (most likely acquired as a co-infection with human adenovirus that is usually required as a 'helper virus' to support AAV2 replication) and disease susceptibility related to HLA class II status.

Impact of increased alcohol consumption during the COVID-19-related lockdowns on admissions with liver disease, gastrointestinal bleeding and pancreatitis in Melbourne, Victoria.

This audit collates data on alcohol-related gastrointestinal (GI) admissions at Monash Health, Victoria, during the prolonged, coronavirus disease 2019 (COVID-19)-related lockdown July to October 2020 compared with the same periods in 2019 and 2021. We found a 58% increase in admissions in 2020 and a 16% increase in 2021, which also increased disproportionately to overall health service emergency presentations. Self-reported alcohol consumption increased by 2.5-fold and was greatest in 2020. Clinical severity was unchanged and cirrhosis was the only factor associated with severe disease. This study suggests an association between the pandemic-related lockdown, alcohol consumption and alcohol-related GI hospitalisation. Our study provides support for resourcing and adapting alcohol and other drug services during and beyond the COVID-19 lockdown.

Our Pediatric Liver and Kidney Transplant Activities in 2021.

OBJECTIVES: In children with end-stage renal disease, chronic liver failure, or acute liver failure, liver transplant and kidney transplant are the most effective modalities for better clinical outcomes compared with other therapies. However, children are particularly susceptible to surgical complications, so pediatric solid-organ transplants should be reserved for centers with substantial experience and multidisciplinary expertise. Here, we assessed liver and kidney transplants performed at our center in 2021. MATERIALS AND METHODS: From November 3, 1975, to December 31, 2021, we performed 701 liver transplants and 3290 kidney transplants. From January 1, 2021, to December 31, 2021, we performed 21 liver transplants (19 in children) and 114 kidney transplants (12 in children). We recorded age, sex, body mass index, comorbidities, etiologies, laboratory values, and clinical outcomes. RESULTS: For the year 2021, we performed 19 pediatric liver transplants and 12 pediatric kidney transplants. Mean age of liver recipients was 3.4 years, and 8 were male patients. The most common etiology was biliary atresia (n = 7). All liver grafts were from living related donors who were first-degree (n = 16) or second- degree (n = 3) relatives of the recipients. Mean hospital stay was 17.6 days. All but 2 liver transplant recipients were discharged successfully (2 died from sepsis in the early postoperative period). Mean age of kidney transplant recipients was 14.1 years, and 4 were male patients. The most common etiology was vesicoureteral reflux (n = 3). One kidney graft was from a deceased donor, with the rest from living related donors who were first-degree relatives of the recipients (n = 11; mother for 8 recipients and father for 3 recipients). Mean hospital stay was 4.3 days. All kidney transplant recipients were discharged successfully. CONCLUSIONS: Solid-organ transplants for young children are often complex but can be performed successfully at experienced transplant centers.

Urinary liver-type fatty acid binding protein is increased in the early stages of the disease with a risk of acute kidney injury induced by histone.

AIM: Urinary liver-type fatty acid binding protein (L-FABP) has potential utility as an early prognostic biomarker ahead of traditional severity scores in coronavirus disease 2019 and sepsis, however, the mechanism of elevated urinary L-FABP in the disease has not been clearly elucidated. We investigated the background mechanisms of urinary L-FABP excretion through non-clinical animal model focusing on histone, which is one of the aggravating factors in these infectious diseases. METHODS: Male Sprague-Dawley rats were placed in central intravenous catheters, and these rats were given a continuous intravenous infusion of 0.25 or 0.5 mg/kg/min calf thymus histones for 240 min from caudal vena cava. RESULTS: After the administration of histone, urinary L-FABP and gene expression of an oxidative stress marker in the kidney increased in a histone dose-dependent manner before increased serum creatinine. Upon further investigation, fibrin deposition in the glomerulus was observed and it tended to be remarkable in the high dose administrated groups. The levels of coagulation factor were significantly changed after the administration of histone, and these were significantly correlated with the levels of urinary L-FABP. CONCLUSIONS: Firstly, it was suggested that histone is one of the causative agents for the urinary L-FABP increase at an early stage of the disease with a risk of acute kidney injury. Secondly, urinary L-FABP could be a marker reflecting the changes of coagulation system and microthrombus caused by histone in the early stage of acute kidney injury before becoming severely ill and maybe a guide to early treatment initiation.

TNFα aggravates detrimental effects of SARS-CoV-2 infection in the liver.

Coronavirus disease 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). This virus does not only lead to pulmonary infection but can also infect other organs such as the gut, the kidney, or the liver. Recent studies confirmed that severe cases of COVID-19 are often associated with liver damage and liver failure, as well as the systemic upregulation of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNFα). However, the impact these immune mediators in the liver have on patient survival during SARS-CoV-2 infection is currently unknown. Here, by performing a post-mortem analysis of 45 patients that died from a SARS-CoV-2 infection, we find that an increased expression of TNFA in the liver is associated with elevated mortality. Using publicly available single-cell sequencing datasets, we determined that Kupffer cells and monocytes are the main sources of this TNFα production. Further analysis revealed that TNFα signaling led to the upregulation of pro-inflammatory genes that are associated with an unfavorable outcome. Moreover, high levels of TNFA in the liver were associated with lower levels of interferon alpha and interferon beta. Thus, TNFα signaling in the infected SARS-CoV-2 liver correlates with reduced interferon levels and overall survival time.

Molecular Mechanism of Chronic Viral and Non-Viral Liver Diseases.

In this Special Issue, "Molecular Mechanism of Chronic Viral and Non-viral Liver Diseases", invaluable articles have been published [...].

COVID-19 related biliary injury: A review of recent literature.

Since its emergence in 2019, it has become apparent that coronavirus 2019 (COVID-19) infection can result in multi systemic involvement. In addition to pulmonary symptoms, hepatobiliary involvement has been widely reported. Extent of hepatic involvement ranges from minor elevation in liver function tests (LFTs) to significant hepatocellular or cholestatic injury. In majority of cases, resolution of hepatic injury or improvement in LFTs is noted as patients recover from COVID-19 infection. However, severe biliary tract injury progressing to liver failure has been reported in patients requiring prolonged intensive care unit stay or mechanical ventilation. Due to the timing of its presentation, this form of progressive cholestatic injury has been referred to as COVID-19 cholangiopathy or post-COVID-19 cholangiopathy, and can result in devastating consequences for patients. COVID-19 cholangiopathy is recognized by dramatic elevation in serum alkaline phosphatase and bilirubin and radiologic evidence of bile duct injury. Cholangiopathy in COVID-19 occurs weeks to months after the initial infection and during the recovery phase. Imaging findings and pathology often resemble bile duct injury associated with primary or secondary sclerosing cholangitis. Etiology of COVID-19 cholangiopathy is unclear. Several mechanisms have been proposed, including direct cholangiocyte injury, vascular compromise, and cytokine release syndromes. This review summarizes existing data on COVID-19 cholangiopathy, including reported cases in the literature, proposed pathophysiology, diagnostic testing, and long-term implications.

Liver Function in Patients with Long-Term Coronavirus Disease 2019 of up to 20 Months: A Cross-Sectional Study.

The long-term laboratory aspects of the effects of coronavirus disease 2019 (COVID-19) on liver function are still not well understood. Therefore, this study aimed to evaluate the hepatic clinical laboratory profile of patients with up to 20 months of long-term COVID-19. A total of 243 patients of both sexes aged 18 years or older admitted during the acute phase of COVID-19 were included in this study. Liver function analysis was performed. Changes were identified in the mean levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), gamma-glutamyl transferase (GGT), and ferritin. A ferritin level of >300 U/L was observed in the group that presented more changes in liver function markers (ALT, AST, and GGT). Age ≥ 60 years, male sex, AST level > 25 U/L, and GGT level ≥ 50 or 32 U/L were associated with an ALT level > 29 U/L. A correlation was found between ALT and AST, LDH, GGT, and ferritin. Our findings suggest that ALT and AST levels may be elevated in patients with long-term COVID-19, especially in those hospitalised during the acute phase. In addition, an ALT level > 29 U/L was associated with changes in the levels of other markers of liver injury, such as LDH, GGT, and ferritin.